The invention relates to a device for the generation of pyrogen controlled water used especially for the preparation of active pharmaceuticals for injectable formulations.
Pyrogen contamination of water used in the production of pharmaceutical products is a major concern of pharmaceutical manufacturers and regulatory authorities. Both chemical and biological pyrogenicity are well-documented and by far the most significant pyrogen within the pharmaceutical industry is bacterial endotoxins.
Bacterial cell associated endotoxins are high molecular weight lipopolysaccharide-protein complexes within an outer membrane of Gram negative bacteria. Endotoxins are ubiquitous and are found in any liquid where Gram negative bacteria are present. They are continually shed into the surrounding environment by the bacteria during cell growth, division, and on cell death, when the bacteria fragment.
Pyrogenic substances produce an increase in body temperature after intravenous injection into man and most animals. Bacterial endotoxins intravenously injected result in the development of fever by inducement of synthesis and release of endogenous pyrogens from host bone marrow derived phagocytic leukocytes. These in turn induce a wide range of chemically harmful events which are manifested in the febrile response.
Methods currently applied in the preparation of high purity water primarily involve distillation or reverse osmosis. Current methods used effectively remove endotoxins by liquid/vapor phase separation and by solute rejection, respectively. There are other methods for the removal of endotoxins in high purity pharmaceutical water systems such as ultrafiltration; however of all the methods currently used, positively charged filter media are unique in utilizing low pore size for selective removal of pyrogen assisted by opposite charge attraction of the negatively charged pyrogen to the filter media. However, the use of such filter media to generate pyrogen controlled water requires stringent control of operation.
The object of the present invention is to provide a portable high purity water unit that utilizes positively charged filter media and which incorporates controls to provide a validated water system on a small to medium scale that has low capital cost, high efficiency, and is easy to use.
According to the invention, there is provided a pyrogen controlled water producing unit for producing pyrogen controlled water on a small to medium factory scale comprising:
(a) a transportable support frame;
(b) a number of filter cartridges, each containing positively charged filter media, the cartridges being mounted to the frame and arranged in parallel, each filter cartridge having an inlet conduit from a common inlet supply and an outlet conduit to a common outlet;
(c) flow restricting means mounted in each filter inlet conduit to control the flow of water through the filter;
(d) a flowmeter in the inlet supply for monitoring the flow of water to the filters;
(e) the inlet supply having a nitrogen purge inlet port for purging the filters and the conduits; and
(f) an outlet port from the common filter outlet at the lowest point in the unit.
In one embodiment of the invention the flow restricting means comprises an orifice plate.
In another embodiment the unit comprises pressure sensor means upstream of the filters for monitoring back pressure from the filters.
Preferably, a pressure sensor is provided in each filter inlet conduit.
Most preferably, the unit comprises at least one sampling port for water sampling.
Ideally, the unit has a sampling port located in the common supply inlet and a sampling port located in the common supply outlet.
The unit preferably comprises a fitting in the common inlet supply for connection to a supply of deionized water. Preferably, the device also includes a fitting in the common outlet for user connection to a pyrogen controlled water supply. The fitting is preferably a quick release coupling.
Preferably the transportable frame has a wheeled chassis. Most preferably the transportable frame has a forklift mounting means.
The invention facilitates close control of flow rates of the water applied to the positively charged filter media. This results in maximum efficiency of endotoxin removal. The unit also facilitates in situ sanitization of the media and pipes together with sterile sampling of the high purity water produced.